Calciphylaxis, beware the ophthalmic mimic: A case series

Purpose: We present two atypical cases of calciphylaxis presenting with ocular ischemic pathology – both without the hallmark cutaneous manifestations – to raise awareness of this rare yet highly disabling condition. Observations: We report two cases of ophthalmic calciphylaxis presenting as (1) anterior ischemic optic neuropathy (AION) and cilioretinal artery occlusion in a 76-year-old woman with pre-dialysis kidney failure, and (2) AION with contralateral central retinal artery occlusion (CRAO) in a 44-year-old man on hemodialysis. Conclusion and importance: These cases highlight the need for judicious clinical suspicion of calciphylaxis in patients with kidney failure, presenting with microvascular ischemic ophthalmic pathology such as AION or CRAO. Confirmation with temporal artery biopsy is essential to direct targeted individualized multi-disciplinary treatment of calciphylaxis and avoid unnecessary steroid exposure in cases masquerading as giant cell arteritis (GCA).

Cutaneous manifestations are the hallmark feature although other vessels can be affected.Calciphylaxis presents with solitary or multiple severely painful cutaneous or subcutaneous lesions (reticulate purpura, indurated plaques, or nodules) involving areas of adiposity that rapidly progress to ulcers with black eschar [1, 2, 5,].Wound infection and sepsis commonly ensue, and calciphylaxis is associated with high morbidity and mortality [3,5].Such typical skin lesions were absent in our reported cases, which instead presented with ophthalmic sequelae of microvascular occlusion and ischemic insult to the optic nerve and retina.Other organs known to be infrequently affected by calciphylaxis include skeletal muscle, intestines, mesentery, heart, penis, pancreas and lungs [1,5].Prognosis is poor, with reported mortality rates of up to 30% at 6 months and between 40 and 80% at 12 months [1,6,7].

Case 1
A 76-year-old female presented with a 4-week history of transient "washed out" color vision and inferior subjective visual field obscuration affecting her left eye.She denied headaches, jaw claudication, or scalp tenderness.Ocular history was significant for moderate bilateral non-proliferative diabetic retinopathy (NPDR) with right vitreomacular traction and left epiretinal membrane with mild macular schisis.She had previously been treated with right scatter photocoagulation.Her medical history was notable for pre-dialysis kidney failure, type 2 diabetes mellitus, hypertension, and hyperlipidemia.
Visual acuity was count fingers (CF) in the left eye and 6/30-1 in her right eye, with a dense left relative afferent pupillary defect (RAPD).She had advanced cataracts bilaterally, and fundal examination demonstrated left optic nerve head swelling, cotton wool spots in the cilioretinal artery distribution, and background bilateral moderate NPDR (Figure 1).Fundus fluorescein angiography (FFA) revealed nasal choroidal non-perfusion, disc leak, and cilioretinal artery occlusion (Figure 2).Her blood pressure was 163/72 mmHg, and bilaterally thickened tortuous non-tender temporal arteries were palpated.She had no cutaneous lesions.
Investigations showed an elevated erythrocyte sedimentation rate (ESR) > 120 mm/h with a normal C-reactive protein (CRP) and  platelet count (4.8 mg/L and 288 × 10 9 /L, respectively).Calcium levels were normal (2.1 mmol/L), phosphate elevated (2.97 mmol/L, range: 0.7 -1.5 mmol/L), creatinine 577 μmol/L, and estimated glomerular filtration rate (eGFR) of 6 mL/min/1.73m 2 , which were consistent with kidney failure.She also had secondary hyperparathyroidism, with a parathyroid hormone (PTH) level at 55.1 pmol/L (range: 0.8 -5.5 pmol/L).There was no evidence of acute cortical ischemia nor significant cervical or intracranial arterial disease on computed tomography scan.Duplex carotid ultrasound showed no significant stenosis.A non-contrast MRI head was unremarkable.Left temporal artery duplex ultrasound showed tortuous small-caliber temporal arteries with heavy calcification of the main trunk extending into the frontal and parietal branches.
With a presumptive diagnosis of AION and given that giant cell arteritis (GCA) could not be excluded, intravenous methylprednisolone was commenced to preserve vision.Initial left temporal artery biopsy (TAB) was equivocal for calciphylaxis, demonstrating marked arterial medial calcification but no inflammatory activity.Repeat TAB on the right confirmed the diagnosis of calciphylaxis, showing severe circumferential arterial calcification and marked intimal thickening, and no convincing evidence of vasculitis (Figure 3).Based on these findings, steroid therapy was promptly tapered and discontinued, hemodialysis was initiated, cholecalciferol supplementation ceased, and lanthanum (non-calcium-based phosphate binder) commenced.Her left eye visual acuity (VA) remained stable (CF).A 44-year-old man presented with acute onset left painless monocular vision loss.His medical history was significant for anti-glomerular basement membrane (anti-GBM) disease complicated by kidney failure.He was receiving hemodialysis for a total of 5 years, with a background of two prior living renal transplants.Severe tertiary hyperparathyroidism had been present for some time, refractory to large doses of cinacalcet.He had well-controlled hypertension, atrial flutter on warfarin for 18 months, and was an active smoker.No prior ocular history was declared.
Visual acuity was hand movements in the left eye, compared to 6/9 in his right eye, with a dense left RAPD.Anterior segments were unremarkable, with fundoscopy demonstrating left inferior pallid disc swelling with a cherry-red macula suggestive of central retinal artery occlusion (CRAO) (Figure 4B).Incidentally, circumferential right optic disc swelling was noted on the contralateral side (Figure 4A).Blood pressure was 120/77 mmHg, and bilaterally thickened non-tender temporal arteries were palpated.No cutaneous lesions were present.
Ancillary testing with Spectral domain optical coherence tomography (SD-OCT) showed marked circumferential thickening of the right retinal nerve fibre layer (RNFL) with macular sparing, and left macula hyperreflectivity with signal increase and loss of distinction of the inner retinal layers (Figure 5).HVF 30-2 demonstrated a right enlarged blind spot and complete loss of visual field in his left eye.FFA demonstrated delayed choroidal filling with disc hyper-fluorescence  and late patchy venous staining in the right eye (Figure 6A).In the left eye, there was significant delayed choroidal filling and delayed arteriovenous transit time (Figure 6B).These findings were indicative of the left AION and right CRAO.
CT brain and CT angiogram showed no evidence of other acute ischemic intracranial pathology, and duplex carotid ultrasound demonstrated bilateral < 50% internal carotid artery stenosis.MRI brain and orbits was not tolerated despite oral sedation due to claustrophobia.Ultrasound of the temporal arteries showed extensive calcific walls and marked tortuosity.Parathyroid ultrasound and nuclear medicine scanning showed parathyroid hyperplasia.Echocardiogram excluded a cardiac thromboembolic source.
Given his younger age and known kidney failure, left TAB (Figure 7) was performed and confirmed calciphylaxis with arterial compromise as the unifying cause of his left CRAO and right AION.As he had developed tertiary hyperparathyroidism refractory to large doses of cinacalcet, he underwent an emergency subtotal parathyroidectomy with histology confirming widespread nodular parathyroid hyperplasia.Post-operatively he was stabilized with a calcium chloride infusion, which was quickly weaned down to oral calcium carbonate and weaning doses of calcium effervescent and calcitriol until calcium levels had stabilized.He was counselled regarding his guarded visual prognosis.Warfarin was ceased, and he was switched to low molecular weight heparin.We elected not to administer sodium thiosulfate as there were no painful cutaneous lesions, nor did he receive hyperbaric oxygen therapy.

Discussion
Calciphylaxis is defined as a metastatic calcification of microvasculature with eventual thrombosis, vessel occlusion, and infarction of affected tissue.Known to predominantly affect arteries, this obliterative vasculopathy can also occur in small arteries and venules, and even capillaries [5].Whilst incompletely understood, it is appreciated that elevated levels of vitamin D, hyperparathyroidism, hyperphosphatemia, and oxidized low-density lipoprotein can trigger the differentiation of vascular smooth muscle cells to produce bone matrix proteins, which precipitate microvascular calcification [1,3,4,5,15].Interestingly, the role of local and systemic hypercoagulable states, including systemic thrombophilia's, is gaining increas-  ing attention in the development of calciphylaxis with the propagation of thrombi in ischemic vessels [3,4].This is further supported by histopathologic findings demonstrating that most patients with calciphylaxis-induced thrombosis had no inflammatory infiltrates suggestive of a vasculitic process [4].This may in part explain why calciphylaxis can also arise in patients with normal kidney function (known as nonuremic calciphylaxis).
A high clinical index of suspicion and histopathological confirmation of calciphylaxis is key for definitive diagnosis, particularly in patients with known kidney failure.Whilst hyperphosphatemia, hypercalcemia, and hypo/hyperparathyroidism are commonly found in those with calciphylaxis, many patients can have normal PTH concentrations [2,5].Calciphylaxis-associated AION, albeit rare, can masquerade as GCA, particularly in the elderly, yet tends to lack the symptoms of jaw claudication, scalp tenderness, and temporal headache typical of GCA.However, the lack of these symptoms does not assist in differentiating the diagnosis, as up to 20% of patients with GCA do not exhibit these typical systemic symptoms [21].ESR is typically elevated in both calciphylaxis-associated AION and GCA [8].Thus, TAB is essential in delineating calciphylaxis from GCA. TAB in GCA typically demonstrates features of chronic granulomatous inflammation including panarteritis with mononuclear cell infiltrates penetrating all layers of the arterial wall, with associated disruption of the elastic layer architecture and intimal hyperplasia [14,15].Whist focal calcification can be present, it is often secondary to atherosclerosis and is not a predominant feature [15].In contrast, calciphylaxis usually demonstrates minimal inflammation with extensive medial artery calcification affecting the entire arteriolar circumference, intimal proliferation, and endovascular fibrosis of small-medium blood vessels [5,15].
The management of calciphylaxis requires a multimodal and multidisciplinary approach, individualized to the patient's clinical presentation.Given the rarity of this disease, the evidence base for calciphylaxis treatment is limited to retrospective data and clinical experience [3].Treatment may involve correcting hyperphosphatemia (e.g., intensification of dialysis sessions, dietary phosphate restriction, use of non-calcium phosphate binders such as sevelamer or lanthanum, hypercalcemia (e.g., cease calciumbased phosphate binders, reduce calcium concentration in dialysis bath), and hyperparathyroidism (e.g., cinacalcet therapy, surgical parathyroidectomy in medically refractory cases) [2, 3 ,4].Supplemental vitamin D and warfarin therapy should be ceased, with consideration of alternative non-vitamin Kdependent anticoagulant therapy (such as apixaban, or heparin) [2,3,4].Conversion from peritoneal dialysis to hemodialysis should also be considered to help improve clearances.Sodium thiosulfate, a calcium chelator, can be used to promote the decalcification of blood vessels [1,2,5].As an antioxidant, sodium thiosulfate may also neutralize reactive oxygen species, thereby reducing inflammation, thrombosis, and vasoconstriction [2,3,5].Hyperbaric oxygen can be useful in aiding wound healing in patients with cutaneous disease but is also an important option for patients who are not surgical candidates for, or have refractory disease following, parathyroidectomy, and those who do not have secondary or tertiary hyperparathyroidism [5].Additionally, hyperbaric oxygen may be of benefit in patients with CRAO if instigated within 24 hours of the onset of visual symptoms [26].

Conclusion
Whilst appreciated to be a cutaneous disease, rarely, calciphylaxis can manifest as ischemic ophthalmic microvascular disease such as AION, CRAO, or ocular ischemic syndrome.Calciphylaxis should be suspected as a differential for patients with kidney failure presenting with AION or CRAO, particularly in younger patients or those lacking the typical systemic symptoms of GCA.Judicious clinical evaluation and histopathological confirmation with a TAB is essential to exclude this life-threatening condition and dictate further management.
The successful treatment of ophthalmic calciphylaxis requires a skilled multidisciplinary effort, tailored to the patient, with close collaboration between physicians and ophthalmologists.Strategies are primarily aimed at stopping the calcification, inhibiting thrombosis, and, in the case of cutaneous disease, wound management and pain control.

Figure 1 .
Figure 1.Color fundus photo of the left eye showing optic nerve head swelling, cotton wool spots along the cilioretinal artery distribution, and background moderate non-proliferative diabetic retinopathy.

Figure 2 .
Figure 2. Fundus fluorescein angiography (FFA) at (A) 17 seconds showing nasal choroidal non-perfusion and (B) 5 minutes, showing disc leakage and late staining at the cilioretinal artery distribution.

Figure 3 .
Figure 3. Temporal artery biopsy showing severe calcification and marked intimal thickening within the media and outer intima.

Figure 4 .
Figure 4. Color fundus photos demonstrating right circumferential (A) optic disc swelling with small superior disc flame hemorrhage and left (B) inferior pallid disc swelling, widespread retinal pallor with a cherry-red macula suggestive of central retinal artery occlusion.

Figure 5 .
Figure 5. Spectral domain optical coherence tomography (SD-OCT) scans of the macula, demonstrating right (A) nasal Retinal nerve fibre layer (RNFL) thickening not involving the macula with normal foveal contour and (B) left macula hyper-reflectivity with signal increase and loss of distinction of the inner retinal layers.

Figure 6 .
Figure 6.Fundus fluorescein angiography (FA) delayed choroidal filling with disc hyper-fluorescence and late patchy venous staining in the right eye (A) and delayed choroidal filling and delayed arteriovenous transit time in the left eye (B).

Figure 7 .
Figure 7. Temporal artery biopsy showing extensive circumferential calcification of the media with some associated intimal hyperplasia.

Table 1 .
Summary of literature describing ocular calciphylaxis.